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2016 Grants - Brett

Structural and Functional Basis for TREM2/ApoE/Lipid Interaction in Alzheimer’s Disease

Thomas John Brett, Ph.D.
Washington University in St. Louis
St. Louis, Missouri

2016 Alzheimer’s Association Research Grant (AARG)

Do certain proteins associated with Alzheimer’s physically interact in ways that may promote disease progression?

Background
Recent studies have shown that certain variations in the genes for apolipoprotein E (APOE) and triggering receptor expressed on myeloid cells 2 (TREM2) may increase the risk for Alzheimer’s disease. Alterations in these genes are thought to affect the production or clearance of beta-amyloid, a protein fragment that accumulates into amyloid plaques in the brain — a hallmark of Alzheimer’s disease. Individuals with the APOE-e4 risk gene tend to have increased levels of beta-amyloid in the brain, but the underlying factors are not yet clear. TREM2 is important for the function of immune cells in the brain called microglia, which are thought to help remove amyloid plaques. Initial studies by Thomas John Brett, Ph.D., and colleagues suggest that the proteins produced by the TREM2 and APOE genes may interact, but more research is needed to better understand how this interaction may impact disease risk.

Research Plan
For their current work, Dr. Brett and colleagues have proposed a series of experiments to determine how the TREM2 protein and different variations of the APOE protein physically interact. They will use novel techniques to isolate the proteins and determine how they bind to each other structurally. Their goal is to determine how TREM2 is affected by different versions of ApoE including: ApoE2 (protective against Alzheimer’s), ApoE3 (normal risk level), and ApoE4 (increased risk of developing Alzheimer’s). Detailed information on how the proteins interact may help explain individual variations in risk, and determine why alterations in their function promote neurodegenerative disease.

Impact
If successful, the results of this research could shed new light on the mechanisms that underlie the complex interaction of Alzheimer’s genetic risk factors. Importantly, these studies could identify potential targets for new therapies to prevent or slow the progression of Alzheimer’s disease.